Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effectiveness of ACE inhibitors in reducing morbidity and mortality in patients with heart failure is largely attributable to their suppression of angiotensin II production. Despite chronic therapy with ACE inhibitors, angiotensin II levels may be incompletely suppressed and contribute to the high mortality of patients with heart failure. Recently, angiotensin receptor blockers, which block the effects rather than the production of angiotensin II, have become available. Angiotensin receptor blockers have been evaluated as both monotherapy and in combination with ACE inhibitors. In short term studies, angiotensin receptor blocker monotherapy appears to share many of the hemodynamic and clinical features of ACE inhibitors. In a long-term study, the Losartan Heart Failure Survival Study, angiotensin receptor blockers failed to demonstrate any beneficial effect over that seen with ACE inhibitors. The addition of an angiotensin receptor blocker to an ACE inhibitor appears to exert favorable short term hemodynamic, clinical, and neurohormonal effects. Four ongoing trials, Valsartan Heart Failure Trial, Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity, Optimal Therapy in Myocardial Infarction with Angiotensin II Antagonist Losartan study, and Valsartan In Acute Myocardial Infarction study, are evaluating the role of angiotensin receptor blockers either alone or in combination with ACE inhibitors in the management of left ventricular dysfunction. (c)2000 by CHF, Inc.
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PMID:The role of angiotensin receptor blockers in heart failure. 1202 95

The renin-angiotensin system exerts a cardinal role in the maintenance of blood pressure and in the regulation of water and sodium excretion through its multiple effects on the vasculature, the kidneys, the heart, the adrenal glands and the brain. Over the last 30 years, blockade of the renin-angiotensin cascade with angiotensin converting enzyme (ACE) inhibitors has proved to be a major advance in the treatment of hypertension and the prevention of its cardiovascular complications. The recent development of specific, orally active angiotensin AT(1) receptor antagonists has provided further insights into the role of the various angiotensin receptor subtypes in the regulation of blood pressure. Even more importantly, these new specific antagonists have provided the opportunity to effectively block the renin-angiotensin system in hypertensive patients with an efficacy comparable to that of other antihypertensive agents but with a tolerability profile similar to that of placebo. Numerous clinical studies have now demonstrated the potential benefits of these agents in the management of essential hypertension. We now need to know whether these agents are capable of reducing the cardiovascular morbidity and mortality associated with hypertension. To this purpose, several large clinical trials are ongoing and we are eager to read their results.
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PMID:[Pathophysiological and clinical implications of AT(1) and AT(2) angiotensin II receptors in essential hypertension]. 1203 86

Based on the data from large single and multi-center clinical trials, including the Heart Outcomes Prevention Evaluation (HOPE) study, it is clear that the presence of microalbuminuria is a signal from the kidney that cardiovascular risk is increased and that vascular responses are altered. This is exemplified by studies that have demonstrated that the compensatory vasodilation seen following relief from prolonged ischemia or infusion of vasodilators such as nitroglycerin is blunted in people with microalbuminuria. Thus, the presence of between 30 and 299 mg/day of albumin in the urine is associated with abnormal vascular responsiveness, which may be the result of more advanced atherosclerosis and not necessarily related to the presence of hypertension or renal disease. Agents known to reduce the rise in microalbuminuria or actually reduce the level of microalbuminuria, such as ACE inhibitors, angiotensin receptor blockers, HMG-CoA reductase inhibitors, beta blockers, non-dihydropyridine calcium channel blockers and diuretics, have all been shown to reduce cardiovascular mortality and in some cases preserve renal function. This article will present an overview of the data that support the assertion that a reduction in the rise of microalbuminuria is a significant consideration in the selection of agents to treat a given risk factor (cholesterol or blood pressure) to a recommended target goal. Achieving such a goal with agents that also impact microalbuminuria will provide for a more complete cardiovascular risk reduction.
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PMID:Microalbuminuria: marker of vascular dysfunction, risk factor for cardiovascular disease. 1208 33

Both ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB) are renoprotective beyond their effects on blood pressure (BP), but their widespread use is limited by their tendency to provoke hyperkalemia. The comparative effects of ACEI and ARB on potassium handling have not been investigated. The objective of this study was to determine whether there are differences in dynamic renal potassium handling between ACEI and ARB in response to an oral potassium challenge. This was a randomized crossover study of candesartan versus lisinopril titrated to control BP followed by an inpatient study of renal potassium handling in 24 hypertensive patients with type II diabetes mellitus (DMII) and preserved renal function. Following an oral potassium challenge (0.75 mmol/kg), differences in hourly serum K (mmol/L), rate of urinary potassium excretion (UkV, micromol/min), and fractional excretion of potassium (FEK) were assessed by repeated-measures ANOVA. Hourly UkV(p = .45) and FEK (p = .19) were similar for candesartan and lisinopril, although FEK at 2 hours for candesartan tended to exceed that for lisinopril (.34 [.04] vs. .26 [.03]) and approached significance (p = .096). UkVfor candesartan at hour 2 was 177 (26) and 121 (21) for lisinopril and also approached significance (p = .10). Serial serum potassium did not differ (p = .70). No statistical differences were discovered in renal potassium handling between candesartan and lisinopril in patients with DMII and preserved renal function. Whether there are differences between the drug classes in renal impairment remains to be determined.
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PMID:Comparative effects on dynamic renal potassium excretion of ACE inhibition versus angiotensin receptor blockade in hypertensive patients with type II diabetes mellitus. 1209 42

The present study was undertaken to clarify the role of intrarenal angiotensin (Ang) II and its generating pathways in clipped and nonclipped kidneys of 4-week unilateral renal artery stenosis in anesthetized dogs. After 4 weeks, renal plasma flow (RPF) decreased in clipped and nonclipped kidneys (baseline, 59+/-3; clipped, 16+/-1; nonclipped, 44+/-2 mL/min; P<0.01, n=22). Renal Ang I levels increased only in clipped, whereas intrarenal Ang II contents were elevated in both clipped (from 0.7+/-0.1 to 2.0+/-0.2 pg/mg tissue) and nonclipped kidneys (from 0.6+/-0.1 to 2.5+/-0.3 pg/mg tissue). Intrarenal ACE activity was increased in nonclipped kidneys but was unaltered in clipped kidneys. An angiotensin receptor antagonist (olmesartan medoxomil) given into the renal artery markedly restored RPF, and dilated both afferent and efferent arterioles (using intravital videomicroscopy). Furthermore, in clipped kidneys, the elevated Ang II was suppressed by a chymase inhibitor, chymostatin (from 2.1+/-0.6 to 0.8+/-0.1 pg/mg tissue; P<0.05), but not by cilazaprilat. In nonclipped kidneys, in contrast, cilazaprilat, but not chymostatin, potently inhibited the intrarenal Ang II generation (from 2.4+/-0.3 to 1.5+/-0.2 pg/mg tissue; P<0.05). Finally, [Pro11-D-Ala12]Ang I (an inactive precursor that yields Ang II by chymase but not by ACE; 1 to 50 nmol/kg) markedly elevated intrarenal Ang II in clipped, but not in nonclipped, kidneys. In conclusion, renal Ang II contents were elevated in both clipped and nonclipped kidneys, which contributed to the altered renal hemodynamics and microvascular tone. Furthermore, the mechanisms for intrarenal Ang II generation differ, and chymase activity is enhanced in clipped kidneys, whereas ACE-mediated Ang II generation is possibly responsible for elevated Ang II contents in nonclipped kidneys.
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PMID:Differential regulation of elevated renal angiotensin II in chronic renal ischemia. 1210 35

African-American patients constitute a significant and important group who are at high risk for developing hypertension-related complications. The proportion of African-American patients succumbing to or suffering from cardiovascular, renal, and neurologic sequelae is unacceptably high. Therefore, it is extremely crucial to develop appropriate therapeutic strategies for this vital subset of our society. The renin-angiotensin system may play a role in the pathophysiology of hypertension-related diseases, and therefore drugs that block this system, ie, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, may have a special indication for African-American patients. Although these drugs may not be the most efficacious agents in terms of blood pressure reduction, they have a major benefit in offering target organ protection and arresting disease progression in the African-Americans. Hence, contrary to the old notions, drugs blocking the renin-angiotension system have an important place in the management of hypertension and related disorders in African-American patients.
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PMID:Are angiotensin converting enzyme inhibitors and angiotensin receptor blockers becoming the treatment of choice in African-Americans? 1211 55

Both basic and experimental data indicate that the renin-angiotensin system through angiotensin II mediates its classic hemodynamic role, but also has a significant deleterious role in a number of cardiac, vascular, and renal disorders. Indeed, evidence indicates that angiotensin II negatively impacts endothelial function, cardiac remodeling, vessel wall hypertrophy, atherosclerosis, and progressive renal disease. Newer data point to a significant role for angiotensin II in inflammation and in inducing plasminogen activator inhibitor. This widespread negative effect can be countered by newer antihypertensive drugs, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers. Both small and large clinical trials suggest a large benefit of such drugs on not only organ-specific endpoints such as renal disease or proteinuria, but on global cardiovascular events. It does appear that when blood pressure is significantly elevated, lowering blood pressure does indeed provide protection for larger endpoints such as stroke. However, at lower blood pressure levels, a hemodynamically independent effect is likely to be contributing to the positive effects. We should embrace these effects and champion them for our patients.
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PMID:Are clinical endpoint benefits of angiotensin converting enzyme inhibitors independent of their blood pressure effects? 1211 56

Clinical trials provide average effects of interventions but are not powered to identify differences in subgroup responses. African-Americans have been under-represented in most previous trials in patients with heart failure. Furthermore, physiologic differences have been demonstrated between African-Americans and whites in the mechanisms and response to therapy in hypertension. Review of previous heart failure trials reveals that African-Americans exhibit less benefit than whites from ACE inhibitors, angiotensin receptor blockers, and at least one b-blocker. In contrast, black patients experienced a greater benefit than white patients from the combination of nitrate and hydralazine. These data emphasize the need for trials in black patients to identify effective therapy. The first such trial, African-American Heart Failure Trial, is currently underway.
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PMID:Contemporary treatment of heart failure: is there adequate evidence to support a unique strategy for African-Americans? Pro position. 1211 58

The attainment of adequate renal protection requires strict blood pressure control and a diminution of proteinuria or microalbuminuria to values as near from normalcy as possible. It has been considered that by getting the first, the second could be attained at the same price. Recent data have confirmed that renal protection in hypertensive patients, diabetics or not, requires combination therapy that has to include an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. A calcium channel blocker can be added to this without renal compromise. A diuretic will also be needed in most cases. Proteinuria will diminish with this combination in particular if up-titration of the drug blocking the effects of angiotensin II is performed. The control of other associated risk factors is also required, in particular smoking and lipids.
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PMID:Renal protection by antihypertensive therapy. 1211 61

Cardiovascular disease is a growing global health threat due in part to demographic shifts, in particular the growing elderly population in which cardiovascular disease is highly likely to develop. Older individuals have numerous coexisting conditions that contribute to increased risk for morbidity and mortality. In the past, physicians primarily used diastolic blood pressure (BP) as the indicator for measuring relative risk. However, since the early 1970s observational studies have found that systolic BP rather than diastolic BP is a better predictor of cardiovascular events, particularly in the older population. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI) recommended specific goals for the treatment of hypertensive patients. Specifically, JNC-VI reinforced the notion of more aggressive BP goals for patients at the greatest risk for an event. The approach to patients who are not at goal is different from earlier guidelines. Therapy is now aimed at building therapeutic regimens. Currently, there are five classes of agents that have been shown to reduce the morbidity and mortality associated with cardiovascular and renal disease: diuretics, beta-blockers, angiotensin converting enzyme inhibitors, calcium antagonists, and angiotensin receptor blockers. If a patient is not at goal and there is no response to an agent from one of these classes or troublesome side effects develop, then and only then should that drug be stopped and a different one used. Otherwise, a multidrug regimen is constructed and additional agents added in logical fashion. A majority of patients with higher risk can attain control at the specified BP goal safely and effectively by using a combination of agents.
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PMID:Risk stratification of older patients. 1212 Oct 9


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